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The specific action of omega-3 fatty acid ethyl esters (OFA) in preventing cerebrovas- cular disease remains unknown, but research has demonstrated multiple ...
Neurology International 2015; volume 7:5809

Omega-3 fatty acid ethyl esters Introduction do not improve clopidogrel associated P2Y12 inhibition in Several trials antiplatelet agents stroke patients Ping Li,1 Haris Kamal,1 Melissa Baxter,2 Bijal K. Mehta3 1Department

of Neurology, Jacob Neurological Institute, University at Buffalo, NY; 2Department of Pharmacy, Buffalo General Medical Center, University at Buffalo, NY; 3Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, Harbor-UCLA Medical Center, Torrance, CA, USA

Abstract The specific action of omega-3 fatty acid ethyl esters (OFA) in preventing cerebrovascular disease remains unknown, but research has demonstrated multiple possible mechanisms. In addition to altering lipid profiles, OFA may inhibit platelet aggregation. Clopidogrel inhibits platelets via the P2Y12 receptor. OFA may alter clopidogrel-associated platelet-inhibition via a possible combined effect on P2Y12 inhibition. To determine if OFA affects clopidogrel associated P2Y12 platelet receptor inhibition by comparing the percentage of responders in patients with cerebrovascular disease who were taking clopidogrel with or without OFA. We retrospectively reviewed data from adult patients with cerebrovascular disease or cerebral aneurysms and taking clopidogrel, who were seen at a single hospital between March 2010 to September 2011. We included 438 subjects in the study. For the 67 subjects who received loading doses of both clopidogrel and OFA, 71.6% had a P2Y12 inhibition response more than 20%, which is considered a positive response. For the 55 subjects who received just clopidogrel load, 67.2% of subjects were responders. There were 70.4% responders in the 274 subjects who were taking 75 mg of clopidogrel alone at home, and 73.8% responders in the 42 subjects who were taking both clopidogrel and OFA at home. However, these percentage differences were not statistically significant. This study did not find additional P2Y12 platelet inhibition when patients were given OFA, either given as a loading dose or taking it daily.

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have confirmed that like aspirin, clopidogrel, and aspirin-dipyridamole do provide secondary stroke prevention.1,2 Therefore, the use of antiplatelet agents is a mainstay of stroke management.3 Although the readily available platelet function tests have made the determination of patients’ responses to certain antiplatelets more objective, their use in management of stroke prevention remains a continued area of research. Additionally, the use of other agents for secondary stroke prevention such as HMG-CoA inhibitors is also considered a valid addition to a post-stroke prevention regime.3,4 In addition to these medications, other over the counter and complementary medicines have been investigated concurrently with these medications. One such class of complementary medicines includes omega-3 fatty acid ethyl esters (OFA), such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Omega-3 fatty acids are a class of fatty acids of essential nutrients, since they cannot be synthesized by humans and must be obtained in the diet. However, most western diets are rich in omega-6 fatty acids and not largely fish derived omage-3 fatty acids. The hypothesized result is that low omega-3 fatty acid diets result in high rates of poor serum lipid profiles and subsequent vascular disease, including stroke and coronary artery disease.5-7 The mechanism of how these fats improve serum lipid proportions and how they contribute to a less inflammatory state continues to be elucidated. One area where omega-3 fatty acids have an effect appears to be platelet aggregation. Omega-3 fatty acids appear to compete with omega-6 fatty acid enzymes that convert omega-3 fatty acids into category 3 thromboxanes and prostaglandins instead of category 1 and 2 thromboxanes and prostaglangins from omega-6 fatty acids. With less thromboxane A2 and more A3, this ultimately leads to less glycoprotein IIb/IIIa signaling resulting less in platelet activation and binding to fibrinogen.5 Also, the P2Y12 receptor on platelets is another mechanism that can amplify the glycoprotein IIb/IIIa integrin signaling. Antiplatelet agents such as aspirin and clopidogrel inhibit the cox-2 enzyme and P2Y12 receptor, respectively, which decreases platelet-platelet aggregation.8 Data in the cardiac literature has shown that there was lower rate of clopidogrel resistance (non-responders) after taking OFA with clopidogrel and aspirin for 30 days compared to those taking clopidogrel and aspirin without OFA.9 Although it is not a common practice, it has been extrapolated to give OFA to clopidogrel non-responders with cerebrovascular dis[Neurology International 2015; 7:5809]

Correspondence: Bijal K. Mehta, Department of Neurology, David Geffen School of Medicine, University of California Los Angeles, HarborUCLA Medical Center, 1000 West Carson Street Torrance, CA 90509, USA Tel.: +1.310.222.3897. E-mail: [email protected] Key words: Omega-3 fatty acid; clopidogrel; P2Y12 receptor; cerebrovascular disease; stroke; DHA; EPA. Contributions: the authors contributed equally. Conflict of interest: the authors declare no potential conflict of interest. Received for publication: 13 January 2015. Accepted for publication: 17 April 2015. This work is licensed under a Creative Commons Attribution NonCommercial 3.0 License (CC BYNC 3.0). ©Copyright P. Li et al., 2015 Licensee PAGEPress, Italy Neurology International 2015; 7:5809 doi:10.4081/ni.2015.5809

ease. The purpose of this study is to determine if OFA use in patients with cerebrovascular disease can improve clopidogrel associated P2Y12 platelet inhibition by comparing: i) the percentage of responders in cerebrovascular disease patients given clopidogrel load along with OFA and patients only receiving loading doses of clopidogrel; ii) the percentage of responders in cerebrovascular disease patients who were taking both a standard dose (75 mg daily) of clopidogrel and OFA with patients only taking the standard dose of clopidogrel at home.

Materials and Methods This is a retrospective chart review study of patients (19 to 98 years old) with cerebrovascular disease or cerebral aneurysms who received clopidogrel in a single high volume stroke center. The study was approved by Health Science IRB of the University at Buffalo. These patients were seen consecutively between March 2010 and September 2011. Only patients who were on clopidogrel prior to arrival to the hospital or started at the hospital for cerebrovascular disease were included in the study. Patients who were taking clopidogrel only for cardiac reasons, patients whose P2Y12 platelet inhibition tests were done prior to the administration of clopidogrel, and those who did not have P2Y12 platelet inhibition test were excluded.

Article Additionally, patients on proton pump inhibitor medications (known competitive inhibitor of clopidogrel metabolism),10 and those who did not have a mediation list on record were excluded. Whether patients were on omega-3 supplementation (either prescription or OverThe-Counter) prior to arrival to the hospital or started in combination with clopidogrel were recorded. From the medical records, demographic information, the dosages of clopidogrel and OFA, and patients’ significant past medical histories were recorded. The VerifyNow P2Y12 point-of-care assay (Accumetrics, San Diego, CA, USA) was used to measure platelet response. VerifyNow P2Y12 is a rapid platelet function assay designed to measure directly the effects of drugs on the P2Y12 receptor. Results of 20% or greater inhibition (PRNL237) was considered as adequate response of platelet inhibition.11 The percentage inhibition was based on P2Y12 Reaction Units (PRU) and Base PRU, with Base as maximal platelet aggregation via thrombin receptor activating peptide pathway. Statistical analysis was performed using Chi-square test for the categorical variables and student’s t-test for the continuous variables. Multiple logistic regression model was used to investigate the effects of OFA on P2Y12 inhibition controlling hypertension (HTN), coronary artery disease (CAD), and dyslipidemia. Significance was defined as P